In neurons genetic information is transmitted from nucleus to synapse in the form of mRNA molecules, which are translated locally in dendritic spines to provide proteins required for learning and memory. In telecommunications multiplexing is used to combine multiple messages into a composite signal for transmission by a single carrier. Recently we discovered that multiplexing is used for transmission of multiple RNAs from nucleus to synapse in neurons. Multiplexing requires a multiplexer (mux) to select individual RNAs and link them together in granules for transport to dendrites and a demultiplexer (demux) to translate individual RNA molecules in granules into proteins required for learning and memory at the synapse. The overall goal of this proposal is to characterize the molecular machinery for multiplexed dendritic targeting of RNAs in neurons and to determine if multiplexing is required for learning and memory. The specific aims are: 1) determine the molecular basis for selection of RNAs for multiplexed dendritic targeting;2) determine the molecular basis for linkage of different RNAs in granules;3) determine the translational output from individual granules at dendritic spines;and 4) determine if multiplexed dendritic targeting of RNAs in the hippocampus is necessary for learning and memory. Characterizing the multiplexing machinery in neurons may reveal potential molecular targets for clinical intervention in neurological diseases that affect learning and memory. PUBLIC HEALTH RELEVANCE: Many (perhaps most) neurological diseases that affect learning and memory do so by disrupting the structure or function of synaptic connections between neurons. The work described in this proposal is focused on understanding how genetic information required for learning and memory is transmitted from the nucleus to the synapse. The results may reveal potential new targets for clinical intervention in neurological disease.